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Fibrinogen

Human Fibrinogen, pdb:3ghg

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Biological Role

The process of haemostasis is crucial to stemming blood loss following vascular injury. It involves a complex balance of pro- and anti-coagulant activities by a multitude of enzymes and cofactors that ultimately lead to a fibrin clot followed by attenuation of the coagulation response to restore normal blood flow. In short, the serine protease thrombin can be thought of as the star player: thrombin cleaves fibrinogen to fibrin (forming the clot) and also activates a trans-glutaminase (Factor XIII) which will create cross-links in the clot to enhance it's tensile strength. Furthermore, upon the formation of the clot thrombin also activates protein C as part of a negative feedback loop, which in turn degrades various cofactors and ultimately shuts down the coagulation response.[1][2]

Fibrinogen, the chief proteinaceous component of a clot, circulates in blood at concentrations genearlly ranging from 2 to 3 mg/mL. Vascular injury exposes tissue factor-bearing subendothelial cells to flowing blood, triggering a coagulation response in order to generate thrombin. This serine protease has a unique specificity for cleavage sites on fibrinogen alpha and beta chains, and when performed it releases fibrinopeptides A and B. This results in the exposure of polymerization sites known as "knobs", which are complementary to "holes" on other fibrinogen molecules. This interaction is non-covalent but strong enough to support the growth of fibrin fibers and ultimately a fibrin clot network capable of stemming blood loss in vivo.[1][2]

Fibrin clots are highly heterogeneous; numerous factors play a role in determining fiber diameter, types of branch points, and number of branching fibers per unit area. Some of these factors are well understood, such as the effects of higher thrombin or fibrinogen concentrations. Others are less understood, such as calcium and metal ion levels, circulating lipid content, coagulation or fibrinolytic protein levels, some studies have even shown smoking and diabetes may change the structural layout or integrity of fibrin clots.[1][2]

Section 2

Section 2

Subsection 1
Subsection 2
Subsection 3
Subsection 4

The of Rad51 has been shown to bind DNA, [1][3][4] and is thought to have significant disordered character.[4] It contains a conserved glycine residue at position 103, although this is not shared by the Drosophila melanogaster Rad51 protein. Mutation of this residue to glutamate results in a greatly reduced ability to bind both ssDNA as well as dsDNA. This defect then leads to a significant reduction in ATPase activity. G103 lies at the surface of the N-terminal domain facing the core ATPase site, yet crystal structures show that G103 is removed from the NTP binding site, so there is no direct interaction that could explain the loss of ATPase activity.[5]

Evolutionary Conservation

References

  1. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Liu
  2. ↑ 2.0 2.1 2.2 Chi P, Van Komen S, Sehorn MG, Sigurdsson S, Sung P. Roles of ATP binding and ATP hydrolysis in human Rad51 recombinase function. DNA Repair (Amst). 2006 Mar 7;5(3):381-91. Epub 2006 Jan 4. PMID:16388992 doi:10.1016/j.dnarep.2005.11.005
  3. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Chen
  4. ↑ 4.0 4.1 Aihara H, Ito Y, Kurumizaka H, Yokoyama S, Shibata T. The N-terminal domain of the human Rad51 protein binds DNA: structure and a DNA binding surface as revealed by NMR. J Mol Biol. 1999 Jul 9;290(2):495-504. PMID:10390347 doi:10.1006/jmbi.1999.2904
  5. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Conway

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